Surgery After Checkpoint Blockade for Selected Patients With Metastatic Melanoma

“In the era of improved systemic therapy, checkpoint blockade for metastatic melanoma and the ability to surgically resect all disease after treatment are associated with survival of 75%, better than what has been previously reported,” Danielle M. Bello, MD, said in summarizing study results during a plenary session at the 2018 Society of Surgical Oncology (SSO) Annual Cancer Symposium in Chicago.1 Dr. Bello is a surgical oncologist at Memorial Sloan Kettering Cancer Center (MSK), New York.

“Surgical resection based on response to checkpoint blockade stratifies groups with the best survival,” Dr. Bello added. “We’ve seen an estimated 5-year overall survival of 90% in patients with stable or responding lesions and 60% for resection of isolated sites of disease progression.”

We’ve seen an estimated 5-year overall survival of 90% in patients with stable or responding lesions and 60% for resection of isolated sites of disease progression.

— Danielle M. Bello, MD

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“Our study aimed to describe the history and outcomes of patients selected for surgery after checkpoint inhibitor therapy,” Dr. Bello said, and the 237 patients in the study constitute a highly selected group. From a total of 1,615 patients included in the MSK melanoma database and treated with checkpoint inhibitors between 2003 to 2017, the researchers identified 596 whose immunotherapy was followed by surgical intervention.

“We excluded patients who were treated with neoadjuvant checkpoint blockade for stage II disease and those who underwent nontherapeutic and diagnostic procedures that did not involve tissue resection,” Dr. Bello explained. “That left us with our 237 patients, who are roughly 15% of the 1,615 patients treated with checkpoint inhibitor therapy.” The majority of patients (162, or 68.5%) had a cutaneous primary melanoma, and 208 patients (88%) had stage IV disease.

SURGERY PLUS IMMUNOTHERAPY IN MELANOMA

Resection to no evidence of disease at the first operation was associated with better survival over patients not resected to no evidence of disease, with median overall survival that was not reached vs 10.8 months, respectively.

Patients resected to no evidence of disease had an estimated 5-year overall survival rate of 75%

“When we looked at the therapy these patients received prior to resection, 62% were treated with anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), suggesting this was an early cohort of patients treated with checkpoint blockade,” Dr. Bello said. In addition, 29% had combination therapy with anti–CTLA-4 and anti–programmed cell death protein 1 (PD-1), either concomitantly or sequentially. Following resection, 48% of patients had no further treatment. Among those who did get additional treatment, 19% received anti–PD-1 therapy alone, and 10% received combination targeted therapy.

The total number of operations among the 237 patients was 348, with 163 patients (70%) having 1 operation and 87 (37%) resected to no evidence of disease. The most common surgeries were resections of skin or soft-tissue metastases, followed by brain or central nervous system lesions.

Stratified by Response to Immunotherapy

Patients werestratified into three categories, based on radiologically assessed response to immunotherapy. In the first category were 12 patients who had an overall response to checkpoint blockade, and their index lesion (ie, the lesion that was resected) was either smaller than it was at the initiation of therapy or was stable.

Armando E. Giuliano, MD

The second category included 106 patients “with an isolated site of progressing disease, in the context of residual stable disease elsewhere or as the only site of progressive disease,” Dr. Bello said. The third category consisted of 119 patients who had multiple sites of disease progression and underwent palliative operations.

In response to a question from session moderator Armando E. Giuliano, MD, Director of Surgical Oncology at Cedars-Sinai Medical Center, Los Angeles, about indications for resection, Dr. Bello said that for those with responding and stable disease, as well as for those with an isolated site of disease progression, “the thought was if they demonstrated a response elsewhere to therapy, this might demonstrate ‘an escape lesion,’ and surgery might improve the outcomes of these patients who have had a systemic response to therapy.”

Survival Outcomes

Median follow-up among all 237 patients was 23 months, whereas the median overall survival was 21 months. Resection to no evidence of disease at the first operation was associated with better survival over patients not resected to no evidence of disease, with a median overall survival that was not reached vs 10.8 months, respectively, Dr. Bello said. “The 87 patients resected to no evidence of disease had an estimated 5-year overall survival rate of 75%; the median overall survival in the no-evidence-of-disease group was not reached.”

As for overall survival stratified by response to immunotherapy, “the patients with responding or stable disease had a 90% 5-year survival. Those with one isolated progressing lesion that was resected had a 60% 5-year overall survival, and the median overall survival was not reached in either of these groups,” Dr. Bello reported. Patients with multifocal progression “not unexpectedly continued to do poorly,” with a median overall survival of 7.3 months (range = 6.2–11.2 months).

More Detailed Look

“We then drilled down and looked in more detail at the patients with the isolated site of progression and stratified them by their resection status,” Dr. Bello said. “Similar to the entire cohort, those who were resected to no evidence of disease had an improved estimated 5-year overall survival of 75%.”

Charlotte E. Ariyan, MD, PhD

The pathologic complete response rate was “low overall in our series at 4%,” Dr. Bello said. “We found that radiologic response did not correlate with [pathologic complete response] in 57% of patients, meaning 8 patients showed disease progression on their imaging studies prior to resection,” Dr. Bello noted. “Interestingly, when you look at the responding or stable lesion category, 6 (50%) of the 12 patients in this group had a [pathologic complete response].”

Dr. Bello advised, “further follow-up is needed to assess the durability and contributions of surgery” to the survival of patients with metastatic melanoma. “Future studies are underway to identify biomarkers associated with improved survival after immunotherapy and surgery.”

Charlotte E. Ariyan, MD, PhD, also a surgical oncologist at MSK, was senior author of the study. ■

DISCLOSURE: Dr. Ariyan is on the advisory board of Bristol-Myers Squibb. Dr. Bello reported no conflicts of interest.